Background and Purpose— Activators of peroxisome proliferator-activated receptor-γ (PPARγ), a member of the PPAR family, increase levels of CuZn-superoxide dismutase (SOD) in cultured endothelium, suggesting a mechanism by which it may exert its protective effect within the brain. These properties raise the question of whether a PPARγ agonist may be neuroprotective in models of ischemia without reperfusion, in which oxidative injury is less prevalent. Methods— In 2 groups of rats, 90 minutes of middle cerebral artery (MCA) occlusion was followed by 1 day of reperfusion, with 1 group receiving pioglitazone (a PPARγ agonist) starting 72 hours before MCA occlusion (MCAO) and continuing through the day of occlusion, whereas the other group received vehicle only. In 2 comparable groups, the MCA was occluded permanently. One day after occlusion, the animals were tested neurologically and infarct volumes were calculated. In a separate group, rats were treated with pioglitazone or vehicle for 4 days. Tissue was obtained from the cortex and the striatum 2 hours into reperfusion after 90 minutes of MCAO, and the tissue was examined for CuZn-SOD by Western blot. Results— Results show a significant reduction in infarct size in the treated rats, with transient MCAO but not permanent MCAO. There was also an improvement in neurological score in the treated animals after transient MCAO. The level of CuZn-SOD was increased in the cortex in treated animals. Conclusions— These data, which show that a PPARγ agonist reduces infarct size in transient but not permanent MCAO, suggest that the role of PPARγ is specific to events occurring during reperfusion. Our data point to CuZn-SOD as the mediator of this neuroprotection.

Objective: To investigate the relationship between weather and headache occurrence using big data from an electronic headache diary smartphone application with recent statistical and deep learning (DL)‐based methods. Background: The relationship between weather and headache occurrence remains unknown. Methods: From a database of 1 million users, data from 4375 users with 336,951 hourly headache events and weather data from December 2020 to November 2021 were analyzed. We developed statistical and DL‐based models to predict the number of hourly headache occurrences mainly from weather factors. Temporal validation was performed using data from December 2019 to November 2020. Apart from the user dataset used in this model development, the physician‐diagnosed headache prevalence was gathered. Results: Of the 40,617 respondents, 15,127/40,617 (37.2%) users experienced physician‐diagnosed migraine, and 2458/40,617 (6.1%) users had physician‐diagnosed non‐migraine headaches. The mean (standard deviation) age of the 4375 filtered users was 34 (11.2) years, and 89.2% were female (3902/4375). Lower barometric pressure ( p < 0.001, gain = 3.9), higher humidity ( p < 0.001, gain = 7.1), more rainfall ( p < 0.001, gain = 3.1), a significant decrease in barometric pressure 6 h before ( p < 0.001, gain = 11.7), higher barometric pressure at 6:00 a.m. on the day ( p < 0.001, gain = 4.6), lower barometric pressure on the next day ( p < 0.001, gain = 6.7), and raw time‐series barometric type I (remaining low around headache attack, p < 0.001, gain = 10.1) and type II (decreasing around headache attack, p < 0.001, gain = 10.1) changes over 6 days, were significantly associated with headache occurrences in both the statistical and DL‐based models. For temporal validation, the root mean squared error (RMSE) was 13.4, and the determination coefficient ( R ² ) was 52.9% for the statistical model. The RMSE was 10.2, and the R ² was 53.7% for the DL‐based model. Conclusions: Using big data, we found that low barometric pressure, barometric pressure changes, higher humidity, and rainfall were associated with an increased number of headache occurrences.

Background: Misdiagnoses of headache disorders are a serious issue. Therefore, we developed an artificial intelligence-based headache diagnosis model using a large questionnaire database in a specialized headache hospital. Methods: Phase 1: We developed an artificial intelligence model based on a retrospective investigation of 4000 patients (2800 training and 1200 test dataset) diagnosed by headache specialists. Phase 2: The model’s efficacy and accuracy were validated. Five non-headache specialists first diagnosed headaches in 50 patients, who were then re-diagnosed using AI. The ground truth was the diagnosis by headache specialists. The diagnostic performance and concordance rates between headache specialists and non-specialists with or without artificial intelligence were evaluated. Results: Phase 1: The model’s macro-average accuracy, sensitivity (recall), specificity, precision, and F values were 76.25%, 56.26%, 92.16%, 61.24%, and 56.88%, respectively, for the test dataset. Phase 2: Five non-specialists diagnosed headaches without artificial intelligence with 46% overall accuracy and 0.212 kappa for the ground truth. The statistically improved values with artificial intelligence were 83.20% and 0.678, respectively. Other diagnostic indexes were also improved. Conclusions: Artificial intelligence improved the non-specialist diagnostic performance. Given the model’s limitations based on the data from a single center and the low diagnostic accuracy for secondary headaches, further data collection and validation are needed.

The purpose of this study was to clarify the kinetics of nitric oxide (NO) induced by either endothelial NO synthase (eNOS) or neuronal NO synthase (nNOS) after transient global forebrain ischemia. We investigated NO production and ischemic changes to hippocampal CA1 neurons in eNOS knockout (-/-) mice and nNOS (-/-) mice during cerebral ischemia and reperfusion. NO production was continuously monitored by in vivo microdialysis. Global forebrain ischemia was produced by occlusion of both common carotid arteries for 10 minutes. Levels of nitrite (NO2-) and nitrate (NO3-), as NO metabolites, in dialysate were determined using the Griess reaction. Two hours after the start of reperfusion, animals were perfused with 4% paraformaldehyde. Hippocampal CA1 neurons were divided into three phases (severely ischemic, moderately ischemic, surviving), and the ratio of surviving neurons to degenerated neurons was calculated as the survival rate. The relative cerebral blood flow (rCBF) was significantly higher in nNOS (-/-) mice than in control mice after reperfusion. Levels of NO3- were significantly lower in eNOS (-/-) mice and nNOS (-/-) mice than in control mice during ischemia and reperfusion. NO3- levels were significantly lower in nNOS (-/-) mice than in eNOS (-/-) mice after the start of reperfusion. Survival rate tended to be higher in nNOS (-/-) mice than in control mice, but not significantly. These in vivo data suggest that NO production in the striatum after reperfusion is closely related to activities of both nNOS and eNOS, and is mainly related to nNOS following reperfusion. Theme: Disorders of the nervous system. Topic: Ischemia.

Background and Purpose— Functional stimulation is accompanied by increases in regional cerebral blood flow which exceed metabolic demands under normal circumstances, but it is unknown whether functional stimulation is beneficial or detrimental in the setting of acute ischemia. The aim of this study was to determine the effect of forepaw stimulation during temporary focal ischemia on neurological and tissue outcome in a rat model of reversible focal forebrain ischemia. Methods— Sprague-Dawley rats were prepared for temporary occlusion of the right middle cerebral artery (MCA) using the filament model. Cerebral blood flow in the MCA territory was continuously monitored with a laser-Doppler flowmeter. Subdermal electrodes were inserted into the dorsal forepaw to stimulate either the forepaw ipsilateral or contralateral to the occlusion starting 1 minute into ischemia and continuing throughout the ischemic period. A neurological evaluation was undertaken after 24 hours of reperfusion, and animals were then euthanized and brain slices stained with 2,3,5-triphenyltetrazolium chloride. Cortical and striatal damage was measured separately. Results— The cortical and striatal infarct volumes were both significantly reduced in the contralateral stimulated group compared with the ipsilateral stimulated group (48% total reduction). There were no statistically significant differences in the neurobehavioral scores between the 2 groups, or in the laser-Doppler flow measurements from the MCA core. Conclusions— Functional stimulation of ischemic tissue may decrease tissue damage and improve outcome from stroke. Although the precise mechanism of this effect remains to be determined, functional stimulation could readily be translated to clinical practice.